The present invention is directed to a thio-containing compound that is capable of inhibiting the enzyme, membrane aminopeptidase P (mAPP or APP), whose natural substrate is bradykinin. The compound is useful as a pharmaceutical agent because by inhibiting bradykinin degradation, the compound allows bradykinin to exert its beneficial effects on the cardiovascular system (including decreasing blood pressure, dilating coronary arteries, providing protective effects on the heart during myocardial ischemia/reperfusion injury, and stimulating formation of new blood vessels), to improve renal function, and to improve glucose tolerance and insulin-sensitivity. The present invention is also directed to a pharmaceutical composition comprising the mAPP inhibitor of the present invention and to a method of inhibiting bradykinin degradation in a mammalian patient, particularly a human patient.
Cardiovascular diseases account for 38% of all deaths in the United States. The most prevalent cardiovascular disorder is hypertension, which currently afflicts 50 million people. Although there has been an improvement in the percentage of hypertensive individuals who are aware of their condition and are being treated, only half of those treated (just 31% of all hypertensives) actually have their blood pressure under control. The difficulty of treating hypertension is evidenced by the fact that more than two-thirds of hypertensive patients require two or more drugs to achieve blood pressure control. Consequently, the development of a new class of drugs will provide additional therapeutic options that can reduce the burden of hypertension and its sequelae.
In addition, more than a million persons in the U.S. have a heart attack each year, resulting in over 500,000 deaths. New medications are needed that can prevent and treat acute myocardial infarction.
One option for treating cardiovascular diseases is to increase the body's concentration of the hormone bradykinin. Bradykinin is known to decrease blood pressure and to protect the heart from ischemic damage. However, this hormone has limited beneficial effects because it is rapidly degraded by aminopeptidase P and angiotensin-converting enzyme (ACE). The ACE inhibitor drugs can potentiate bradykinin by inhibiting its degradation. Some of the blood pressure lowering effects and most of the acute cardioprotective effects of ACE inhibitors are due to this mechanism. Angiotensin II receptor antagonists also act in part through bradykinin, since they increase the activation of the AT2 receptor, which in turn stimulates bradykinin release from endothelial cells.
A novel alternative method was devised for increasing bradykinin levels, namely, inhibiting aminopeptidase P (U.S. Pat. No. 5,656,603; William H. Simmons, Ph.D., inventor; Loyola University Chicago, assignee). The prototype aminopeptidase P inhibitor, apstatin (Formula I), was shown to reduce bradykinin degradation in the isolated perfused rat heart and lung. Apstatin enhanced the blood pressure-lowering
effects of intravenously administered bradykinin. In a rat model of severe hypertension, apstatin acted synergistically with an ACE inhibitor to reduce blood pressure to normal. [Kitamura et al. “Effects of aminopeptidase P inhibition on kinin-mediated vasodepressor responses,” Am. J. Physiol., 276, H1664-H1671 (1999)] mAPP inhibition with apstatin also exhibited cardioprotective effects; in a heart attack model using an isolated perfused heart, apstatin reduced cardiac damage by 74%. [Ersahin et al., “Cardioprotective effects of the aminopeptidase P inhibitor apstatin: studies on ischemia/reperfusion injury in the isolated rat heart,” J. Cardiovasc. Pharmacol., 34, 604-611 (1999)] It reduced reperfusion-induced ventricular fibrillation by a similar amount. Subsequent studies in other laboratories showed that inhibiting mAPP by administering apstatin substantially reduced myocardial infarct size in intact rats subjected to regional cardiac ischemia. [Wolfrum et al., “Apstatin, a selective inhibitor of aminopeptidase P, reduces myocardial infarct size by a kinin-dependent pathway,” Br. J. Pharmacol., 134, 370-374 (2001); Veeravalli et al., “Infarct size limiting effect of apstatin alone and in combination with enalapril, lisinopril and ramiprilat in rats with experimental myocardial infarction,” Pharmacol. Res., 48, 557-563 (2003)]
Apstatin has excellent pharmacological properties, exhibits reasonable potency (micromolar), and has good specificity and metabolic stability. However, it has chemical properties that limit its usefulness as an orally active drug. Although apstatin and related compounds have potential as injectable drugs, the potency and predicted intestinal absorption rate are probably too low to allow them to be effective following oral administration. Therefore, it is an object of the present invention to discover mAPP inhibitors having greater potency (i.e., a lower IC50) than apstatin such that they can be administered in lower dosages as injectable drugs, and/or that because of their potency and chemical structure can be administered in an orally acceptable form.